A natural modulator of AMPK signaling regulating lipid metabolism in a steatosis model

Non-alcoholic fatty liver disease (NAFLD) is a metabolic disorder characterized by excessive lipid accumulation in hepatocytes and impaired lipid degradation. In its early stages, NAFLD is considered reversible, and targeting key metabolic pathways represents a promising therapeutic strategy. Plants are a valuable source of bioactive molecules with beneficial effects in metabolic and chronic diseases.Here, we investigated the metabolic effects of a natural flavonoid extracted from Glycyrrhiza glabra leaves, known for its anti-inflammatory and antioxidant properties, in an in vitro model of steatosis. In HepG2 cells overloaded with oleic and palmitic acids, the compound activated AMP- activated protein kinase (AMPK), a central regulator of lipid metabolism, and significantly reduced intracellular lipid droplet accumulation. Kinome profiling revealed activation of kinases involved in metabolic regulation, autophagy, and stress response. Functional validation showed enhanced mitochondrial activity (Seahorse analysis) and improved oxidative stress resistance, accompanied by nuclear accumulation of Nrf2. Furthermore, autophagy activation was confirmed through LC3 puncta analysis. In summary, this natural compound exerts protective metabolic effects in steatotic hepatocytes by activating AMPK, stimulating autophagy, enhancing mitochondrial function, and boosting antioxidant defenses. These findings support its potential as a promising therapeutic agent for early-stage NAFLD.